Alkoxymethyl and benzyloxymethyl phenobarbital compounds

ABSTRACT

Various derivatives of barbituric acid and of diphenylhydantoin are described in which alkoxymethyl or benzyloxymethyl groups are attached to the nitrogen atoms of the rings. Therapeutic compositions containing these compounds and their use as anti-convulsant agents are described.

This application is a continuation in part of application Ser. No.749,972, filed Aug. 5, 1968, now abandoned.

This invention relates to selected substituted barbituric acids andhydantoins, to the use thereof as anticonvulsant agents for treatingconvulsions and seizures in warm-blooded animals, and to therapeuticcompositions containing these compounds. More particularly, thisinvention relates to 1,3-dialkoxy(ordibenzyloxy)methyl-5,5-disubstituted barbituric acids having the formula##STR1## wherein R and R₁ are phenyl and ethyl respectively, or R and R₁are individually alkyl or alkenyl each having 2 to 5 carbon atoms orcycloalkenyl having 5 to 7 carbon atoms, and wherein R₂ and R₃ areindividually alkyl having 1 to 12 carbon atoms or benzyl; and to3-alkoxymethyl-5,5-diphenyhydantoin or1,3-dialkoxymethyl-5,5-diphenylhydantoin or3-benzyloxymethyl-5,5-diphenylhydantoin.

Phenobarbital and diphenylhydantoin have both long been known to beuseful as anticonvulsant agents in warm-blooded animals, having beenemployed in the treatment of epilepsy; however, phenobarbital suffersfrom the disadvantage that it exhibits hypnotic activity as well asanticonvulsant activity, while diphenylhydantoin has the disadvantagethat although not hypnotic, it does have a multiplicity of undesirableside effects, for example, hypertrophic gingivitis, megaloblasticanemia, toxic psychoses, and hirsutism. It has been found that N-loweralkoxymethyl phenobarbital and N-lower alkoxymethyl diphenylhydantoincompounds are effective anticonvulsants which possess unexpectedadvantages from the pharmacological standpoint over their respectiveparent compounds.

Although it has been reported in Doran, Medicinal Chemistry, New York1959, Volume IV John Wiley & Sons, Inc. page 187 (War Department ArmyMedical Library, Microfilm No. 1720, I. G. Farbenindustrie Plant,Elberfeld, Germany) that a material identified by the structural formulaof N,N'-dimethoxymethyl phenobarbital has been tested as a hypnotic andfound to be without effect, there has been no indication that it has anyuseful therapeutic effect and no suggestion as to how to make it or whatits properties are.

The compounds of the present invention are effective anticonvulsantagents for convulsions and seizures in warm-blooded animals and are freefrom hypnotic activity as hereinafter described. The compounds in whichthe alkoxy groups are methoxy or ethoxy are preferred;N,N'-dimethoxymethyl phenobarbital, and 3-methoxymethyldiphenylhydantoin are particularly preferred.

The compounds may be made by reacting an appropriate (e.g. alkali metalsalt) barbiturate, such as phenobarbital sodium, or diphenylhydantoinsodium, with chloromethyl or other halomethyl alkyl or benzyl ether in asuitable diluent such as dimethyl formamide, dimethyl sulfoxide,dimethyl acetamide, hexamethylphosphoramide, and the like over a widerange of temperatures, conveniently from about -10° C. up to the boilingpoint of the diluent. The desired products are obtained in high yieldand in an excellent state of purity; they can conveniently be isolatedby conventional techniques such as extraction, distillation, filtration,preparative chromatography, etc.

Illustrative substituted barbituric acids which are employed in saltform to prepare compounds of the present invention include the followingcommercially available compounds: barbital, phenobarbital, probarbital,aprobarbital, amobarbital, allobarbital, vinbarbital, pentobarbital,cyclobarbital, 5-allyl-5-(2-cyclopentenyl)barbituric acid,5-ethyl-5-cycloheptenyl barbituric acid, etc. Diphenylhydantoin sodiummay also be used.

Among the halomethyl alkyl or benzyl ethers suitable for use in thepreparation of the compounds of the present invention are chloromethylmethyl ether, chloromethyl ethyl ether, chloromethyl butyl ether,chloromethyl n-dodecyl ether, chloromethyl benzyl ether, and the like.

The compounds of the invention can be formulated with conventionalphysiologically acceptable vehicles and carriers to make syrups,isotonic solutions, tablets and other dosage forms. Toxicity andeffectiveness of the compounds are such that each dosage unit cancontain from 5 to 500 mg of active material. However, in view of thehigh anticonvulsant activity of these compounds, dosage units containingfrom 5 to 200 mg of the compound are preferred.

The procedures employed for demonstrating efficacy of the compounds asset forth in the following examples were as follows.

All tests, with the exceptions noted, were conducted on adult albinomale mice (Charles River strain); the dosage consisted of the activeagent suspended in 10% aqueous acacia and was administered orally unlessotherwise indicated.

Acute oral toxicity and acute intraperitoneal toxicity were determinedin the conventional manner. The results were expressed as LD₅₀, the doserequired to produce death in 50% of the animals treated, determinedgraphically, with the 95% limits shown in parentheses.

The dosage required to produce a neurological deficit was determined bythe method of Swinyard et al., J. Pharmacol. Exptl. Therap. 106, 319(1952) except that one additional test was employed: the ability of theanimal to remain for at least one minute on a "rotorod", a horizontalrod rotated at 6 r.p.m. The results were expressed as TD₅₀, the doserequired to produce the effect, determined graphically, with 95% limits.

Anticonvulsant effectiveness of each agent against maximal electroshockwas determined at the time of peak effect. The time of peakanticonvulsant activity was determined by administering dosages ofvarious sizes to a group of animals and administering a maximalelectroshock to the animals at intervals thereafter by supply 60 ma.current through a corneal electrode for 0.2 second. Protection wasindicated if the animal failed to show the tonic extensor component ofthe maximal electroshock seizure pattern in unprotected animals. Thetime of peak effect thus determined was used for all subsequent tests ofanticonvulsant activity on the same active agent.

Anticonvulsant effectiveness was determined against a convulsive dose ofMetrazol (106.25 mg/kg) injected subcutaneously; the criterior foreffectiveness was failure to show clonic convulsive seizures.Anticonvulsant activity was determined against a lethal dose ofstrychnine sulfate (1.5 mg/kg) injected subcutaneously; the criterionwas failure to die, even though seizures appeared.

Hypnotic activity or depression of the central nervous system asindicated by loss of the righting reflex (onset of sleep) was notexhibited by any dosage of any of the compounds of the present inventionless than a lethal dose. Phenobarbital itself, on the other hand, didexhibit hypnotic activity using the foregoing criterion.

The following examples will serve to illustrate the practice of thisinvention.

EXAMPLE 1

In a 1000 ml flask equipped with a stirrer and condenser, 136.4 g.(0.536 mole) of phenobarbital sodium powder was suspended in 500 ml ofdimethylformamide. The flask was placed in an ice bath. To the coldsuspension was added 100 g. (1.25 mole) of chloromethyl methyl etherover a period of one hour. The resulting suspension was stirred at roomtemperature for twenty hours, then poured into 2000 ml of ice water andthe resulting suspension was stirred for two hours. The crude productwas removed by filtration, and washed three times with 100 ml ofdistilled water, then dissolved in about 500 ml of hot ethanol. To theboiling solution 1 g. of activated carbon was added and the boilingsolution was filtered through a Buchner funnel which contained a 1 cm.pressed layer of finely-divided diatomaceous silica. The cake was washedthree times with 25 ml of ethanol and the hot solution together with thewashings was allowed to cool to room temperature. The resulting crystalswere filtered, washed with ethanol, and dried in a vacuum desiccator.There was obtained 58 g. of N,N'-dimethoxymethyl phenobarbital (alsoknown as 1,3-dimethoxymethyl-5-ethyl-5-phenyl barbituric acid), meltingpoint 115°-117° C.

Pharmacological testing of this compound gave the following results:

    ______________________________________                                                            Dosage, mg/kg                                             ______________________________________                                        Acute Toxicity                                                                 LD.sub.50 (oral)     470 (376-588)                                            LD.sub.50 (intraperitoneal)                                                                        490 408-588)                                            Neurological Deficit                                                           TD.sub.50            47 (33-66)                                              Anticonvulsant Activity                                                        Maximal electroshock, ED.sub.50                                                                    13.5 (8-23)                                              Metrazol, ED.sub.50  47 (29-75)                                               Strychnine, ED.sub.50                                                                              200 (125-320)                                           Time of peak activity 2 hours                                                 ______________________________________                                    

Repeated daily dosage of the same animals for four days showed nosignificant change in the ED₅₀ to protect against maximal electroshock.The duration of the anticonvulsant effect against maximal electroshockwas compared with that of phenobarbital sodium at a dosage level of 0.1millimole/kg of each. The compound of this example protected only aftertwo hours, but protection continued at about the same level for morethan eight hours. Phenobarbital provided protection in less than 0.5hour, but protection began to decrease after four hours and was nearlygone by eight hours.

Anticonvulsant activity of the compound against maximal electroshock wasalso measured in the rat (Sprague Dawley Strain); the ED₅₀ was found tobe 6.6 (4.2-10.4).

EXAMPLE 2

5,5-Diphenylhydantoin sodium (27.5 g., 0.1 mole) was suspended in 250 mlof dimethylformamide. To the suspension was added over a period of 30minutes 8.8 g. (8.25 ml) of chloromethyl methyl ether. The resultingsuspension was stirred at room temperature overnight, then poured into 1liter of ice water. A solid material precipitated. The suspension wasstirred for one hour and the solid was removed by filtration, washed onthe filter three times with 100 ml of water, and the wet cake wasdissolved in 125 ml of ethanol with heating. To the boiling solution 1g. of activated carbon was added and the boiling solution was filteredthrough a Buchner funnel containing a 1 cm pressed layer offinely-divided diatomaceous silica. The cake was washed three times with15 ml of ethanol and the hot ethanol solution together with the washingswas diluted with 100 ml of hot water, then allowed to cool to roomtemperature. The crystals which appeared were filtered and washed threetimes on the filter with 25 ml of 50% aqueous ethanol, then dried in avacuum desiccator. There was obtained 20 g. of3-methoxymethyl-5,5-diphenylhydantoin; m.p. 127°-128° (yield 67%).Pharmacological testing of this compound showed it to have LD₅₀ ofapproximately 500 mg/kg. It exhibited anticonvulsant activity (maximalelectroshock) within less than 0.5 hour after ingestion, and theactivity lasted for more than 2 hours; the ED₅₀ was less than 25 mg/kg.

EXAMPLE 3

Powdered phenobarbital sodium (25 g.) was suspended in 250 ml ofdimethylformamide. With vigorous stirring 15.6 g of chloromethylbenzyl-ether was added to the suspension at room temperature. Thereaction mixture was stirred overnight at room temperature. Thesuspension was then poured into 500 g of ice cold water, the mixture wasstirred for one hour and the solid removed by filtration. The crudeproduct was dissolved in about 150 ml boiling ethanol; to the boilingsolution 0.5 gram of activated carbon was added, and the boilingsolution was filtered through a Buchner funnel which contained acompacted layer of finely-divided diatomaceous silica. The cake waswashed three times with 10 ml of ethanol and the hot solution togetherwith the washings was allowed to cool to room temperature. The resultingcrystals were filtered and recrystallized from 100 ml of ethanol in thesame manner as described for the first crystallization. There wasobtained 5.27 g of N,N'-dibenzyloxymethyl phenobarbital (also known as1,3-dibenzyloxymethyl-5-ethyl-5-phenyl barbituric acid), m.p. 74°-75°.

EXAMPLE 4

Powdered phenobarbital sodium (25 g.) was suspended in 350 ml ofdimethylformamide. With vigorous stirring 15 g ofchloromethyl-(n)-butyl-ether was added to the suspension at roomtemperature. The suspension was stirred overnight at room temperature.The reaction mixture was then poured into 1 kg of ice cold water, themixture was stirred for one hour, and the solid removed by filtration.The crude product was dissolved in hot ethanol (100 ml), 1 g ofactivated carbon was added and the boiling solution was filtered througha Buchner funnel which contained a compacted layer of finely-divideddiatomaceous silica. The cake was washed three times with 10 ml ofethanol and the hot solution together with the washings was allowed tocool to room temperature. The resulting crystals were filtered andrecrystallized two more times from 100 ml of ethanol in the same manneras described for the first crystallization. There was obtained 12.3 g ofN,N'-di-(n)-butoxymethyl phenobarbital (also known as1,3-di-(n)-butoxymethyl-5-ethyl-5-phenyl barbituric acid), m.p. 71°-72°C. When tested as described above the compound exhibited anticonvulsantactivity against maximal electroshock, the ED₅₀ being less than 100mg/kg; and an LD₅₀ (oral) greater than 500 mg/kg.

EXAMPLE 5

Phenobarbital sodium (25 g) was dissolved in 250 ml of dimethylformamideat 120° C. The solution was cooled to 60° and at this temperature 25 gof chloromethylethylether was added with good stirring. The reactionmixture was allowed to cool to room temperature and stirred for 20hours, then poured into 500 g of ice water, stirred for one hour, andthe solid product was removed by filtration. The solid material wasdissolved in 150 ml of boiling ethanol, 1 g of activated carbon wasadded and the boiling solution was filtered through a Buchner funnelwhich contained a compacted layer of finely-divided diatomaceous silica.The cake was washed three times with 10 ml of ethanol and to the hotsolution together with the washings there was added 50 ml of hot waterand the solution was allowed to cool to room temperature. The resultingcrystals were filtered and recrystallized two more times in the samemanner as described for the first crystallization. There was obtained6.5 g of N,N'-diethoxymethyl phenobarbital (also known as1,3-diethoxymethyl-5-ethyl-5-phenyl barbituric acid), m.p. 65°-65°. Whentested as described above, the compound exhibited anticonvulsantactivity against maximal electroshock, the time of peak activity being11/2 hours and the ED₅₀ being less than 25 mg/kg.

EXAMPLE 6

5,5-Diphenylhydantoin sodium (27.5 g) was suspended in 250 ml ofdimethylformamide at 100° C. The suspension was cooled to 50° C. withgood stirring. At this temperature 16 g of chloromethyl-(n)-butyletherwas added and the suspension was stirred for three hours while allowingthe temperature to drop to 20° C. The reaction mixture was then pouredinto 1 liter of ice cold water and stirred for one hour. The resultingsolid product was removed by filtration and dissolved in 150 ml of hotethanol; 1 g of activated carbon was added and the boling solution wasfiltered through a Buchner funnel which contained a compacted layer offinely-divided diatomaceous silica. The cake was washed three times with10 ml of ethanol and the hot solution together with the washings wasallowed to cool to room temperature. The resulting crystals werefiltered and recrystallized two more times in the same manner asdescribed for the first crystallization. There was obtained 8.9 g of3-(n)-butoxymethyl-5,5-diphenylhydantoin, m.p. 108°-110°. Upon testingas described above, the compound exhibited anticonvulsant activityagainst maximal electroshock, the ED₅₀ being less than 25 mg/kg. TheLD₅₀ (oral) was also determined to be greater than 500 mg/kg.

EXAMPLE 7

5,5-Diphenylhydantoin sodium (27.5 g) was suspended in 250 ml ofdimethylformamide. To the suspension was added 15 ml ofchloromethylbenzylether with good stirring and the mixture was stirredat room temperature overnight. The reaction mixture was then poured into1 liter of ice cold water and stirred for one hour. The solid productwas removed by filtration and dissolved in 150 ml of hot ethanol. To theboiling solution 1 g of activated carbon was added and the hot solutionwas filtered through a Buchner funnel which contained a compacted layerof finely-divided diatomaceous silica. The cake was washed three timeswith 10 ml of ethanol and the hot solution together with the washingswas allowed to cool to room temperature. The resulting crystals werefiltered and recrystallized two more times in the same manner asdescribed for the first crystallization. There was obtained 13.1 g of3-benzyloxymethyl-5,5-diphenylhydantoin, m.p. 151°-152°.

EXAMPLE 8

Powdered phenobarbital sodium (25.4 g) was suspended at room temperaturein 250 ml of dimethylformamide and 22.1 g of chloromethyldodecanyl etherwas added to the suspension. The reaction mixture was stirred overnightand poured into 1 liter of ice-water; the mixture was then stirred for 3hours and the waxy solid removed by filtration. The wet solid wasdissolved in 150 ml of boiling ethanol; to the hot solution 1 g ofactivated carbon was added and the boiling solution was filtered througha Buchner funnel which contained a compacted layer of finely-divideddiatomaceous silica. The filter cake was washed three times with 15 mlof ethanol and the hot solution together with the washings was allowedto cool overnight. The resulting crystals were filtered andrecrystallized in the same manner as described for the firstcrystallization. There was obtained 13 g of N,N'-dilauryloxymethylphenobarbital (also known as 1,3-dilauryloxymethyl-5-ethyl-5-phenylbarbituric acid), m.p. 48°-50°. When tested as described above thecompound exhibited anticonvulsant activity against maximal electroshock,the peak activity occurring at 2 hours and the ED₅₀ being about 50mg/kg. The LD₅₀ (oral) was determined to be greater than 500 mg/kg.

EXAMPLE 9

Sodium barbital (41.2 g.; 0.200 mole) was suspended in 200 cc ofdimethylformamide in a 500 ml flask equipped with a stirrer andcondenser. Chloromethyl methyl ether (32.0 g.; 0.400 mole) was addedgradually over a period of 15 minutes, with stirring, to the sodiumbarbital slurry. The resulting mixture was stirred for four hours andthen poured into 1000 ml of ice water. After stirring for an additionalhour, the reaction mixture was extracted with ethyl acetate. The ethylacetate solution was dried and the ethyl acetate was evaporated underreduced pressure to provide an oil. Purification was carried out bycolumn chromatography using 60-200 mesh silica gel. Elution with asolvent mixture containing 1 part of ethyl acetate and 9 parts ofbenzene (by volume) yielded 1,3-dimethoxymethyl-5,5-diethyl-barbituricacid.

Analysis calculated for C₁₂ H₂₀ N₂ O₅ : C, 52.93, H, 7.40; N, 10.29;Found: C, 53.07; H, 7.51; N, 10.35.

Pharmacological testing of this compound gave the following results:

    ______________________________________                                        Acute Toxicity                                                                 LD.sub.50 (oral)    >1000 mg/kg                                               LD.sub.50 (intraperitoneal)                                                                       ca 1000 mg/kg                                            Anticonvulsant Activity                                                       Metrazol, ED.sub.50  7(4.6-8.4) mg/kg                                         Time of Peak Activity                                                                              1 hour                                                   ______________________________________                                    

EXAMPLE 10

Sodium barbital (4.0 g.) was suspended in 50 ml of dimethylformamide. Tothe suspension was added, over a period of 5 minutes, chloromethyln-dodecyl ether (10 g.). The suspension was heated at 110° C. for aperiod of 1 hour and then allowed to stand overnight without heating.The suspension was poured into 500 ml of ice water and the resultingaqueous emulsion was extracted with ethyl acetate. The ethyl acetatesolution was dried and the ethyl acetate was evaporated under reducedpressure to yield an oil, which was purified by column chromatographyusing silica gel (70-325 mesh). Elution with benzene provided1,3-di-n-dodecyloxymethyl-5,5-diethyl barbituric acid.

Analysis calculated for C₃₄ H₆₄ N₂ O₅ : C, 70.30; H, 11.11; N, 4.82;Found: C, 70.56; H, 11.17; N, 4.67.

When tested as described above, this compound exhibited anticonvulsantactivity against Metrazol, the ED₅₀ being about 200 mg/kg; a time ofpeak activity of about one hour and an LD₅₀ (oral) of more than 1000mg/kg.

EXAMPLE 11

Sodium secobarbital (25.5 g) was suspended in dimethylformamide (250ml.) The suspension was stirred vigorously and chloromethyl methyl ether(8.5 ml) was added over a period of 10 minutes. The reaction mixture wasstirred at room temperature overnight, then poured into ice water andthe oily product extracted into methylene chloride. The methylenechloride solution was dried, and the methylene chloride evaporated underreduced pressure to yield a crude oil. Purification by columnchromatography using silica gel (60-200 mesh) and elution with a solventmixture containing 1 part of ethyl acetate and 9 parts of benzene (byvolume) provided 1,3-dimethoxymethyl-5-allyl-5-(2-pentyl) barbituricacid.

Analysis calculated for C₁₆ H₂₆ O₅ N₂ : C, 58.88; H, 8.03; N, 8.58;Found: C, 58.93; H, 8.13; N, 8.60.

Upon testing as previously described, the compound exhibitedanticonvulsant activity against Metrazol, the ED₅₀ being about 100 mg/kgand an LD₅₀ (oral) of >500 mg/kg.

EXAMPLE 12

Sodium secobarbital (25.5 g.) was dissolved in 250 ml of hotdimethylformamide. The solution was vigorously stirred and allowed tocool to room temperature to provide a fine suspension. To the suspensionwas added chloromethyl benzyl ether (16.5 g.) over a period of 10minutes. The reaction mixture was stirred overnight and poured into 500ml of ice water; the mixture was stirred for 1 hour and was extractedinto methylene chloride. The methylene chloride solution was dried andthe methylene chloride evaporated under reduced pressure to yield anoil. This crude oil was adsorbed on 60-200 mesh silica gel; elution witha solvent mixture containing 1 part of ethyl acetate and 20 parts ofbenzene (by volume) provided pure1,3-dibenzyloxymethyl-5-allyl-5-(2-pentyl) barbituric acid.

Analysis calculated for C₂₈ H₃₄ O₅ N₂ : C, 70.27; H, 7.16; N, 5.85;Found: C, 70.34; H, 7.16; N, 5.67.

When tested as described above, this compound exhibited anticonvulsantactivity against Metrazol, the ED₅₀ being about 200 mg/kg and had anLD₅₀ (oral) of more than 1000 mg/kg.

What is claimed is:
 1. A compound having the structure ##STR2## whereinR and R₁ are individually alkyl or alkenyl each having 2 to 5 carbonatoms or cycloalkenyl having 5 to 7 carbon atoms, and wherein R₂ and R₃are individually alkyl having 1 to 12 carbon atoms or benzyl.
 2. Acompound as claimed in claim 1 which is 1,3-dimethoxymethyl-5,5-diethylbarbituric acid.
 3. A compound as claimed in claim 1 which is1,3-di-n-dodecyloxymethyl-5,5-diethyl barbituric acid.
 4. A compound asclaimed in claim 1 which is 1,3-dimethoxymethyl-5-allyl-5-(2-pentyl)barbituric acid.
 5. A compound as claimed in claim 1 which is1,3-dibenzyloxymethyl-5-allyl-5-(2-pentyl) barbituric acid.